Non-globular proteins (NGPs) encompass different molecular phenomena that defy the traditional sequence-structure-function paradigm. NGPs include intrinsically disordered regions, tandem repeats, aggregating domains, low-complexity sequences and transmembrane domains. Although growing evidence suggests that NGPs are central to many human diseases, functional annotation is very limited. It was recently estimated that close to 40 of all residues in the human proteome lack functional annotation and many of these are NGPs. While a better understanding of NGPs is crucial to fully comprehend human molecular physiopathology, progress has been hampered so far by the lack of a systematic approach to their study.This Action Proposal aims to create a pan-European scientific network of groups that work on NGPs to strengthen, focus and coordinate research in this field. It proposes to develop a novel classification of NGPs by consensus among interested experts that will be showcased on a newly developed web site, along with meetings, training schools and scientific missions on NGP-related topics.

Duration:

31.5.2015 – 25.3.2019

BIOMARKAPD – Biomarkery pre Alzheimerovu a Parkinsonovu chorobu

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Program:

Multilateral – other

Project leader:

Doc. MVDr. Žilka Norbert DrSc.

Annotation:

Neurodegenerative disorders, represented mostly by Alzheimer’s disease (AD) and Parkinson’sdisease (PD), are characterised by progressive neuronal impairment and death. In spite of the brain’sknown capacity for regeneration, lost neurons generally cannot be replaced. Therefore, drugs aimedat inhibiting neurodegenerative processes are likely to be most effective if the treatment is initiated asearly as possible in the disease process. However, clinical manifestations in early disease stages areoften difficult to diagnose. This is where biomarkers, specifically reflecting the onset of pathology mayhave a profound impact on diagnosis and detection of treatment effects in the near future. A triplet ofcerebrospinal fluid (CSF) biomarkers for AD, total and hyperphosphorylated tau that reflect AD-typeaxonal degeneration, and the 42 amino acid isoform of amyloid beta that reflects senile plaque pathology, has already been established for early detection of AD before the onset of dementia. With regards to PD, the most promising biomarker is CSF alpha-synuclein. However, large variations in all biomarker measurements have been reported between studies, both between and within centres andlaboratories. Such variations may be caused by pre-analytical, analytical, or assay-related factors andseriously jeopardize the introduction of biomarkers in clinical routine and trials around the world.

Etiopathogenesis of neurodegenerative diseases: focus on RNA processing regulation in development and progression of sporadic tauopathies and Alzheimer´s disease

Program:

SRDA

Project leader:

doc. RNDr. Filipčík Peter CSc.

Duration:

1.10.2013 – 30.9.2016

ŠTÚDIUM FUNKCIE TAU PROTEÍNU V JADRÁCH NEURÓNOV

Studies of tau protein functions in nuclei of neurons

Program:

VEGA

Project leader:

Mgr. Baráth Peter PhD.

Annotation:

Neurofibrillary tangles, one of the hallmarks of Alzheimer\’s disease (AD),are composed of missfolded tau protein that belongs to the family of microtubule-associated proteins. The transition between normal and pathological tau proteins is driven by post-translational modifications and partial proteolytic cleavage. It is generally assumed that the main function of tau involves regulation of the dynamics of neuronal microtubules. Recently, this typical cytosolic protein has been shown to translocate to the nucleus where it might participate in DNA protection upon stress. Within the project, we will study nuclear tau shuttling mechanism using cellular models expressing truncated forms, some of which cause development of AD-like symptoms in transgenic rat. We will also explore the mechanism of DNA protection that includes description of nuclear tau interactome and FISH analysis of chromosomal regions recognized by tau. The study will provide new perspective on physiological and pathological roles of tau protein.

Identification of the posttranslational modifications of the neuronal protein tau leading to neurofibrillary degeneration in tauopathies

Program:

SRDA

Project leader:

Mgr. Kováčech Branislav PhD.

Annotation:

Neurofibrillary degeneration consisting of misfolded neuronal protein tau is the key pathological feature of tauopathies, affecting about 13% of people over the age of 65 and half of those over 85 in the developed countries. The extent of the tau pathology directly correlates with the clinical progression of the disease. It is assumed that halting the tau misfolding process in neurofibrillary pathology would lead to successful therapies preventing the cognitive decline. Hyperphosphorylation and truncation of tau are thought to play the principal role in the induction of its pathology. However, the identity and temporal order of the individual phosphorylation events (there are 45 confirmed phospho-sites on tau) that are required for its misfolding have not been revealed, yet. Furthermore, the temporal relationship of truncation and phosphorylation events on tau is also unknown. In this project we will address the question of the identity and temporal order of the individual phosphorylation patterns and truncation events in the misfolding process of normal tau protein into insoluble aggregates. We will use a unique rat model faithfully reproducing all aspects of the complete cascade of human neurofibrillary degeneration. The results will thus provide a clue for the understanding the paradox how can a highly soluble structureless flexible protein turn insoluble and highly structured in the disease.